tbuckley/cabot-search huggingface dataset:
MODL-21. EFFICACY OF DIFFERENT LAYOUTS IN TREATING INFRATENTORIAL TUMORS WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Ariel Naveh, Tal Marciano
Journal: Neuro-Oncology (2022)

Abstract TTFields are an anti-mitotic technique used to treat solid tumors by delivering low-intensity (1–4 V/cm) alternating electric fields to the tumor, with frequencies between 100–500 kHz. This modality is FDA-approved for treating glioblastoma (GBM). Administration of TTFields is conducted using two pairs of transducer arrays placed on the patient’s scalp. The layouts of the transducer arrays is a key factor in determining the field distribution within the patient’s body. The NovoTAL system is used for determining the array layouts used for supratentorial tumors. In previous works, we suggested layouts for infratentorial layouts, as well as layouts that target the entirety of the brain with field distribution of higher uniformity. However, in some clinical cases, patients may have an infratentorial tumor and a single supratentorial tumor simultaneously. In such a situation, the question of whether we can treat both tumors with an infratentorial layout arises. In this work, we examined all GBM available layouts (NovoTAL, infratentorial and whole brain). We used a realistic healthy patient model (Duke, by ITI’S, Zurich, Switzerland) to assess field distributions resulting for the different layouts. We then created maps of expected TTFields dose for a 10 cm sized tumor placed in each point in the brain, and ranked the different regions by best layout groups. Our results show that for infra-ventricular tumors, the whole brain layouts may provide higher field distributions than any of the NovoTAL or infratentorial layouts. For supra-ventricular tumors, NovoTAL layouts provide stronger fields. A transition zone in which both layout groups provided similar results was observed as well. We conclude that the best option of currently available transducer array layouts for treating the presented clinical case depends on the location of the supratentorial tumor, whether it is above the large ventricles or beneath them.
TMIC-31. ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION
Authors: Jake Symington, Richard Perryman, Sophie Morse, Kevin O'Neill, Elizabeth Want, Nelofer Syed
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is a primary brain tumour with poor prognosis and limited treatment options. We previously demonstrated that arginine deprivation by ADI-PEG20 is effective in GBM tumors which are auxotrophic for arginine. We also reported that ADI-PEG20 has efficacy in arginine non-auxotrophic GBM when combined with radiation in the presence of an immune competent environment. Here, we present detailed mechanistic insight into our latter findings using multiplex Imaging Mass Cytometry (Fluidigm) and Spatial Transcriptomics (10x Genomics) of tumor samples treated with ADI-PEG20. ADI-PEG20 enhanced the expression on MHC class II on infiltrating CD11c+ dendritic cells and these cells colocalised specifically with CD4+ T cells. We also observed changes in the expression of PD-1/PD-L1 with ADI-PEG20 and this was further enhanced when ADI-PEG20 was combined with radiation. Moreover, combination therapy increased the expression of chemokines involved in immune cell recruitment and activation. Our findings demonstrate that arginine deprivation restores immune function in the tumor microenvironment of arginine non-auxotrophic GBM tumors and suggests that combinations with immunotherapies will further enhance efficacy for GBM tumors.
TMIC-43. HEDGEHOG LIGANDS FROM GLIOBLASTOMA CELLS INDUCE ASTROCYTES INHIBITION OF CANCER STEM CELLS
Authors: Kyounghee Seo, S John Liu, Vikas Daggubati, Joanna J Phillips, Jennifer Clarke, Michael Prados, Aparna Bhaduri, Daniel Lim, Erik Ullian, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The Hedgehog pathway directs gene expression programs that are essential for glioblastoma stem cells in vitro, but a clinical trial suggested Hedgehog pathway inhibition does not improve glioblastoma outcomes (ABTC-0904). In pancreatic and bladder cancer, Hedgehog signaling through the tumor microenvironment induces stromal morphogens to inhibit cancer stem cell proliferation. Thus, we hypothesized Hedgehog signaling through the glioblastoma microenvironment may inhibit glioblastoma stem cell proliferation in vivo. METHODS Hedgehog signaling was studied using patient-derived, fluorescently-labeled IDH wild-type glioblastoma cells (GBM6, SF11956, SF11907, GPMP004, GPMP005) in vitro, in vivo after intracranial implantation in mice, or in 3D co-culture with iPSC-derived organoids comprised of human astrocytes or neurons. Genetic loss-of-function experiments were performed using CRISPR interference. Cell proliferation, stem cell marker expression, Sonic Hedgehog (SHH) expression, or primary cilia architecture were assessed using immunofluorescence, confocal microscopy, or live-cell imaging. Hedgehog signaling or morphogen expression were assessed using QPCR or single-cell RNA sequencing. Pharmacologic experiments were performed using vismodegib to inhibit the Hedgehog pathway, or FK506 to induce stromal morphogen expression. RESULTS Vismodegib increased glioblastoma cell proliferation and stem cell marker expression in vivo or in co-culture with astrocyte organoids. Single-cell RNA sequencing demonstrated glioblastoma cell co-culture with astrocyte organoids induced Hedgehog target genes and stem cell markers in glioblastoma cells, or stromal morphogens in astrocytes, which also expressed primary cilia. CRISPRi suppression of SHH in glioblastoma cells increased glioblastoma cell proliferation and stem cell marker expression in co-culture with astrocyte organoids. Neither vismodegib nor SHH suppression induced glioblastoma cell proliferation or stem cell marker expression in vitro or in co-culture with neuron organoids. FK506 induced astrocyte morphogen expression, inhibiting glioblastoma cell proliferation, stem cell marker expression, and the effects of vismodegib in co-culture with astrocyte organoids. CONCLUSIONS SHH from glioblastoma cells signals through astrocytes to inhibit cancer stem cell proliferation.
MODL-02. GLIOMA ORGANOID MODEL PHENOTYPICALLY RECAPITULATES KEY ASPECTS OF MALIGNANT TRANSFORMATION IN GLIOBLASTOMA
Authors: Yi Zhao, Shiva Kant, Pravin Kesarwani, Christopher Hubert, Ichiro Nakano, Joseph Fullmer, Prakash Chinnaiyan
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) displays extensive intra-tumoral heterogeneity, serving as a major obstacle for effective treatment. The identification of molecular subtypes offered promise for personalized treatment regimens in GBM, however, it has seen been determined these subtypes are reflective of intra- rather than inter-tumoral heterogeneity, with proneural (PN) and mesenchymal (MES) subtypes corresponding to the infiltrative edge and peri-necrotic core of a tumor, respectively. Further, plasticity between subtypes has been identified, with PN-to-MES transition being described as a mode of resistance. Our laboratory utilizes patient-derived, subtype-specific GBM neurospheres as a model to understand GBM heterogeneity and have previously demonstrated that these models faithfully recapitulate human disease, with PN-neurospheres expressing Olig2, having a metabolic phenotype consistent with low-grade glioma, and an indolent growth pattern in vivo when compared to aggressive, CD44 expressing MES-neurospheres. In parallel, our group demonstrated 3D-organoid models of GBM recapitulate the tumor ecology of this malignancy ex vivo. Therefore, we sought to determine if this model could be utilized to provide a window into the plasticity of GBM molecular subtypes. Consistent with their phenotype when grown as neurospheres, MES-organoids had a homogeneous distribution of proliferating cells and retained CD44 expression. In contrast, cellular heterogeneity emerged in PN organoids that could be morphologically divided into an outer, cell-dense rim and an inner core with a lower cell density. The outer rim, recapitulating a perivascular niche, contained proliferating cells, and the inner core contained necrotic cells, mimicking the hypoxic microenvironment of GBM. Intriguingly, PN organoids retained Olig2 expression in the edge, however, actively transitioned into a MES-like state in the core, expressing CD44 and metabolic reprogramming consistent with malignant transformation. Collectively, these finding support that microenvironment contributes towards PN-MES transition and PN organoid models may serve as a tool to provide a window into specific molecular and metabolic factors contributing towards transformation.
TMIC-19. NEURODEVELOPMENTAL SUBTYPES SHAPE LIPID METABOLIC REPROGRAMMING IN GLIOMAS
Authors: Jenna Minami, Nicholas Bayley, Christopher Tse, Henan Zhu, Jennifer Salinas, Danielle Morrow, William Yong, Timothy Cloughesy, Linda M Liau, Thomas G Graeber, David Nathanson
Journal: Neuro-Oncology (2022)

Abstract Gliomas have been classified into molecular (proneural, classical, mesenchymal) and neurodevelopmental (astrocyte, mesenchymal, neural progenitor cell (NPC), oligodendrocyte progenitor cell (OPC)) subtypes describing inter- and intra-tumoral heterogeneity; however, the functional outcomes and therapeutic implications of these subtypes has yet to be fully described. Metabolic reprogramming is a hallmark of cancer, and malignant cells, including gliomas, acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype, mutations) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Altered metabolism in glioma is of particular interest given the extensive molecular heterogeneity of tumors, while also developing in the brain microenvironment, a tissue known for its unique metabolic milieu. It is unknown whether neurodevelopmental subtypes influence metabolism in gliomas. Preliminary comprehensive lipidomic and transcriptomic analysis of over 200 patient-derived glioma samples revealed that distinct lipid signatures were linked to neurodevelopmental subtypes. Specifically, proneural-like gliomas (OPC, NPC, Neuron) had a lipid metabolic profile enriched in ether lipids. Conversely, mesenchymal-like gliomas (radial glia, MES.progenitor, vascular) have a lipid metabolic profile enriched in triacylglycerides (TAGs). Intriguingly, these differences in lipid metabolic programs between subtypes were associated with environmental dependencies; in contrast to more mesenchymal like gliomas, which could grow irrespective of tumor microenvironment (brain or in vitro cell culture), the proneural-like gliomas required features of the brain microenvironment to accumulate complex fatty acids and grow. Collectively, these data emphasize the metabolic heterogeneity within gliomas, and reveal a subset of gliomas that lack metabolic plasticity in fatty acid biosynthetic programs, indicating a potential brain-microenvironment specific metabolic dependency linked to transcriptional identity that may be targeted for therapy.
SURG-37. NEURO-ONCOLOGICAL AUGMENTED REALITY: A MORE INTUITIVE APPROACH TO RESECTION PLANNING
Authors: Frederick Van Gestel, Taylor Frantz, Quentin Neuville, Sam Klein, Michaël Bruneau, Bart Jansen, Thierry Scheerlinck, Jef Vandemeulebroucke, Johnny Duerinck
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND When preparing for the resection of an intracranial lesion, its borders and optimal approach are often determined using neuronavigation with a tracked pointer. This can sometimes prove challenging, especially for deep-seated lesions. Augmented reality (AR) can simplify and improve this step by directly displaying the lesion on the patient's skin. METHODS A proprietary inside-out infrared tracking solution was developed, allowing for heads-up displaying AR scenes on the Microsoft HoloLens II without the need for an external tracking camera or computer. We included twenty patients with an intracerebral lesion planned for resection. After semi-automatic hologram-to-patient registration, different participants marked the lesion outlines on the patient’s skin, consecutively aided by the Brainlab neuronavigation system and the HoloLens. Each registration on both systems provided a registration transform that was compared for accuracy and consistency. Participant performance was quantified in terms of duration and accuracy for both patient registration and lesion delineation, and compared to expert performance. RESULTS When using AR both registration and delineation were significantly faster than with conventional neuronavigation (p = 0.02 and p &amp;lt; 0.001, respectively, and p &amp;lt; 0.001 for the total duration), taking 79.23 ± 17.48 and 39.58 ± 39.10 seconds while neuronavigation required 96.61 ± 24.54 and 90.80 ± 44.09 seconds. AR had a registration offset of 3.3mm and 3.4°, and was more consistent compared to neuronavigation. AR facilitated more accurate and detailed lesion delineation, while neuronavigation often overestimated lesion size. CONCLUSION Augmented reality provides a faster and more accurate alternative for resection planning. Lesion delineation was more intuitive while retaining high accuracy. Future research should focus on further intraoperative implementations.
TMIC-23. EXPLORING IBRUTINIB'S EFFECTS ON BLOOD-BRAIN BARRIER INTEGRITY AND GLIOMA PROGRESSION
Authors: Mahalia Dalmage, Nabanita Kundu, Minhye Kwak, Sanghee Lim, Sadhana Jackson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The blood-brain barrier (BBB), among malignant gliomas limits certain agents from impairing tumor growth. Thus, identifying agents that can transiently increase BBB permeability may prove useful in enhancing glioma treatment response. Previous ibrutinib studies showed it independently disrupted gut epithelial integrity and hampered glioma growth through BMX (bone marrow x-linked tyrosine kinase) inhibition. We propose BMX inhibition via ibrutinib disrupts BBB integrity while impairing glioma progression. METHODS To evaluate ibrutinib’s effect on brain endothelium, we evaluated electrical cell-cell impedance, junctional/cytoskeletal expression, downstream protein expression and functional ABC transporter activity; monitoring changes over time (0 to 8h) and at varied drug concentrations (1-10μM ibrutinib). Using rat glioma cells (S635) in vitro and in models, we examined cytotoxicity, apoptosis, model survival, and drug concentrations with ibrutinib alone or combined with poorly permeable Abcb1 substrate doxorubicin. RESULTS Ibrutinib dose-dependently decreased brain endothelial cell-cell impedance by 60% at 2h, without affecting cell viability. We observed decreased ZO-1 junctions, actin cytoskeletal rearrangement, and downstream pErk and pMek decreased expression optimally 2h (10μM ibrutinib). Dose-dependently ibrutinib inhibited Abcb1 efflux activity, further favoring a more permeable endothelium. Synergy with doxorubicin was seen in rat glioma cells treated with ibrutinib via increased apoptosis and cytotoxicity. However, while combined treatment resulted in decreased systemic doxorubicin concentrations, no differences in brain:plasma or tumor:plasma concentrations were evident. Combination therapy also did not increase rodent glioma model survival nor decrease tumor size. CONCLUSION Our results suggest that while ibrutinib induces brain endothelial permeability by junctional/cytoskeletal disruption and inhibition of Abcb1 efflux, no sustained effect can be seen in rodent glioma models in combination with a cytotoxic agent. Additional studies exploring similar agents that can enhance BBB permeability while slowing glioma growth are warranted, so as to improve upon current bleak malignant glioma treatment options.
TMIC-74. THERAPEUTICALLY REPROGRAMMING MICROGLIA TO ANTI-TUMORAL ACTIVATION STATES IN DIFFUSE MIDLINE GLIOMA, H3K27 MUTANT
Authors: Lily Keane, Mercedes Posada Perez, Lara Friess, Bertrand Joseph
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG), H3K27M mutant, is one of the most challenging paediatric cancers to date with poor treatment options and dismal survival outcomes. Therefore, new treatment options are desperately needed. Previously we found that activation of the microglial tumour-supportive phenotype by DIPG is associated with a transient H3K27me3 downregulation suggesting a role for this pathway in inducing this activation state. However, it should be noted, that microglia do not carry the H3-K27M mutation when analysed in DIPG patient tissue, otherwise characteristic of the cancer cells. Ezh2 is a histone methyltransferase and the catalytic subunit of the polycomb repressor complex 2 (PRC2), responsible for tri-methylation of histone H3 at lysine 27. We found that repression of Ezh2 in microglia induced an anti-tumour phenotype resulting in decreased cancer cell invasion capability, increased microglial phagocytosis, and tumour-related cell death. Antisense RNA strategies were used to target Ezh2 gene expression in BV2 microglia and we have now carried out RNA sequencing on scramble BV2 or siEzh2 microglia co-cultured with DIPG tumour cells to further understand how EZH2, PRC2 and H3K27me3 regulates DIPG-induced microglia activation. Further work has found that activation of the microglial tumour supportive phenotype, in this context, is determined by a complex epigenetic mechanism involving both H3K4me3 and H3K27me3 and their associated methyltransferases. These histone marks are often associated with bivalent regulation of distinct gene transcription programs, and we are currently investigating if this is the case for DIPG-induced activation states using chromatin immunoprecipitation techniques. Overall, our results indicate that microglia, can be reprogrammed epigenetically by EZH2 inhibition to exert anti-tumoral responses and that microglia represent a new therapeutic avenue in DIPG. This future work should provide novel mechanisms governing pro-tumoral microglial activation states and new therapeutic targets that can be combined with EZH2 inhibition to enhance anti-tumoral microglia activation states.
SURG-34. INTRAOPERATIVE CORTICOBULBAR MOTOR EVOKED POTENTIALS RELIABLY PREDICT FACIAL NERVE FUNCTION IN ELDERLY PATIENTS WITH CEREBELLOPONTINE ANGLE TUMORS. A CLINICAL AND NEUROPHYSIOLOGY STUDY
Authors: Giuseppe M Della Pepa, Vito Stifano, Quintino Giorgio D'Alessandris, Grazia Menna, Benedetta Burattini, Michele Di Domenico, Alessandro Izzo, Manuela D'Ercole, Rina Di Bonaventura, Liverana Lauretti, Alessandro Olivi, Nicola Montano
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Cerebellopontine angle (CPA) surgery for extra-axial lesions in elderly patients could be hampered by concerns regarding functional outcomes. However, an overall ageing society warrants an improved approach. Intraoperative neuromonitoring is crucial for facial nerve (FN) preservation: intraoperative cortico-bulbar facial motor evoked potentials (FMEPs) can be effectively coupled to standard techniques. In a previous work, we validated the use of FMEPs as preditors of early and late post-operative FN function (FNF). Aim of this study was to re-evaluate FMEP role in patients beyond 65 years of age. METHODS An institutional series of 83 patients was reported. A pair of needle electrodes was used to record FMEP from orbicularis oculi (OOc) and orbicularis oris (OOr) muscles; baseline, final and minimum values were recorded. From FMEP amplitudes, minimum-to-baseline (MBR) and final-to-baseline (FBR) amplitude ratios, and recovery value (RV=FBR-MBR), were calculated. These indices were correlated to early (at discharge) and late (at 1-year) post-operative FNF. RESULTS 23 (27.7%) patients were older than 65 years. Among these, 52.2% and 81% had a good early and late FNF, respectively. Early and late FNF were not associated to age (p &amp;gt; 0.99 and p=0.72, respectively). In elderly patients, higher FBR (from OOc and OOr) and MBR (from OOc) were associated to a good early FN recovery (p=0.01, p=0.009, and p=0.03, respectively). Conversely, MBR from OOr was the only parameter significantly associated with late FN function (p=0.049). ROC analysis confirmed that, in elderly patients, the most accurate index for predicting late FN function was MBR as measured from OOr (AUC=0.869, cut-off value 12.5%). The most accurate index for predicting early FN function was FBR from OOc (AUC=0.865). CONCLUSION Cortico-bulbar FMEPs are reliable predictors of early and late post-operative FNF in elderly patients and allow a safe and feasible surgery in this important cohort.
Progression of frailty as measured by a cumulative deficit index: A systematic review
Authors: Daliya Kaskirbayeva, Robert West, Hussain Jaafari, Natalie King, Daniel Howdon, Farag Shuweihdi, Andrew Clegg, Silviya Nikolova
Journal: Ageing Research Reviews (2022)

Frailty is a risk factor for adverse health outcomes. There is a paucity of literature on frailty progression defined by a cumulative deficit model among community dwelling older people. The objective of this review was to synthesise evidence on these changes in health and mortality among community-dwelling older people.Six databases (Medline, Embase, CINAHL, Cochrane, PsycInfo, Web of Science) and a clinical trials registry were searched in July 2021. The inclusion criteria were studies using a frailty index and providing information on transition between frailty states or to death in community-dwelling older people aged ≥ 50. Exclusion criteria were studies examining specific health conditions, conference abstracts and non-English studies. To standardise the follow-up period and facilitate comparison, we converted the transition probabilities to annual transition rates.Two reviewers independently screened 5078 studies and 61 studies were included for analysis. Of these, only three used the same frailty state cut-points to facilitate cross-cohort comparison. This review found that frailty tends to increase with time, people who are frail at baseline have greater likelihood to progress in frailty and die, and the main factor that accelerates frailty progression is age. Other risk factors for progression are having chronic disease, smoking, obesity, low-income or/and low-education levels. A frailty index is an accurate predictor of adverse outcomes and death.This systematic review demonstrated that worsening in frailty was a common frailty transition, and older people who are frail at baseline are more likely to die. A frailty index has significant power to predict adverse health outcomes. It is a useful tool for within-cohort comparison but there are challenges comparing different cohorts due to dependence of frailty progression on age and differences in how frailty index is defined and measured.
A multicenter descriptive analysis of 270 men with frontal fibrosing alopecia and lichen planopilaris in the United States
Authors: James T. Pathoulas, Kelly E. Flanagan, Chloe J. Walker, Maya S. Collins, Shaheir Ali, Isabel M. Pupo Wiss, George Cotsarelis, Heather Milbar, Kathie Huang, Arash Mostaghimi, Deborah Scott, Jane J. Han, Karen J. Lee, Maria K. Hordinsky, Ronda S. Farah, Gretchen Bellefeuille, Ora Raymond, Wilma Bergfeld, Geraldine Ranasinghe, Jerry Shapiro, Kristen I. Lo Sicco, Daniel Gutierrez, Justin Ko, Paradi Mirmirani, Natasha Mesinkovska, Katerina L. Yale, Lynne J. Goldberg, Antonella Tosti, Eran C. Gwillim, Carolyn Goh, Maryanne M. Senna
Journal: Journal of the American Academy of Dermatology (2022)
Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth
Authors: Hongyun Zhao, Da Teng, Lifeng Yang, Xincheng Xu, Jiajia Chen, Tengjia Jiang, Austin Y. Feng, Yaqing Zhang, Dennie T. Frederick, Lei Gu, Li Cai, John M. Asara, Marina Pasca di Magliano, Genevieve M. Boland, Keith T. Flaherty, Kenneth D. Swanson, David Liu, Joshua D. Rabinowitz, Bin Zheng
Journal: Nature Metabolism (2022)
Cardiac fibroblasts and mechanosensation in heart development, health and disease
Authors: Maurizio Pesce, Georg N. Duda, Giancarlo Forte, Henrique Girao, Angel Raya, Pere Roca-Cusachs, Joost P. G. Sluijter, Carsten Tschöpe, Sophie Van Linthout
Journal: Nature Reviews Cardiology (2022)